HOPE in Action Trial of HIV+ Deceased Donor Liver Transplants for HIV+ Recipients

Johns Hopkins University80 enrolled

Overview

The primary objective of this study is to determine if an HIV-infected donor liver (HIVD+) transplant is safe with regards to major transplant-related and HIV-related complications

This study will evaluate if receiving a liver transplant from an HIV-infected deceased liver donor is safe with regards to survival and major transplant-related and HIV-related complications compared to receiving a liver from an HIV-uninfected deceased liver donor (HIVD-). Those participants who have accepted an HIVD- organ will be randomized to be followed in the full study or followed in the nested observational group

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Hiv

Interventions

HIVD+/R+OTHER

Liver from an HIV-infected deceased donor

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participant meets the standard criteria for liver transplant at the local center. * Participants being listed for a simultaneous liver kidney (SLK) are eligible if participants meet the standard criteria for both organs. * Participant is able to understand and provide informed consent. * Participant meets with an independent advocate per the HIV Organ Policy Equity (HOPE) Act Safeguards and Research Criteria. * Documented HIV infection (by any licensed assay or documented history of detectable HIV-1 RNA).\* * Participant is ≥ 18 years old. * Opportunistic complications: prior history of certain opportunistic infections is not an exclusion if the participant has received appropriate therapy and has no evidence of active disease. Medical record documentation should be provided whenever possible. * CD4+ T-cell count: ≥ 100/µL within 16 weeks prior to transplant if no history of AIDS-defining infection; or ≥ 200 μL if history of opportunistic infection is present. * HIV-1 RNA is below 50 RNA/mL.\* Viral blips between 50-400 copies will be allowed as long as there are not consecutive measurements \> 200 copies/mL. \*Organ recipients who are unable to tolerate anti-retroviral therapy (ART) due to organ. failure or recently started ART may be eligible despite a detectable viral load if safe and effective ART to be used by the recipient after transplantation is described. * Participant must have or be willing to start seeing a primary medical care provider with expertise in HIV management. * Participant is willing to comply with all medications related to participant's transplant and HIV management. * For participants with a history of aspergillus colonization or disease, no current clinical evidence of active disease. * Agreement to use contraception. * Participant is not suffering from significant wasting (e.g. body mass index \< 21) thought to be related to HIV disease. Exclusion Criteria: * Participant has a history of progressive multifocal leukoencephalopathy (PML), or primary central nervous system (CNS) lymphoma.\* * Participant is pregnant or breastfeeding. (Note: Participants who become pregnant post-transplant will continue to be followed in the study and will be managed per local site practice. Women that become pregnant should not breastfeed.) * Past or current medical problems or findings from medical history, physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Locations (26)

Outcomes

Primary Outcomes

Time to first death or graft failure or serious adverse event (SAE) or HIV breakthrough or opportunistic infection as a composite measure

Time (in days) to first of any of the following events: death or graft failure or SAE or HIV breakthrough or opportunistic infection

Time frame: From date of transplant through administrative censorship at study completion, up to 4 years

Secondary Outcomes

Time to Pre-transplant mortality

Time (in days) to mortality while enrolled before transplant (survival framework)

Time frame: From date of enrollment to date of transplant or death of any cause, whichever comes first, assessed up to 4 years

Graft Failure as assessed by Time to first occurrence of mortality or re-transplant or return to maintenance dialysis

Time (in days) to mortality or re-transplant or return to maintenance dialysis (survival framework)

Time frame: From date of transplant through administrative censorship at study completion, up to 4 years

1-year acute liver rejection

Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2016 comprehensive Update for antibody mediated rejection and Banff 1997 criteria for acute cellular rejection, liver.

Time frame: From date of transplant to end of year 1

2-year acute liver rejection

Time frame: From date of transplant to end of year 2

3-year acute liver rejection

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

University of Alabama, Birmingham

Birmingham, Alabama, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

University of California, San Diego

San Diego, California, United States

University of California, San Francisco

San Francisco, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

MedStar Georgetown Transplant Institute

Washington D.C., District of Columbia, United States

University of Miami

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

...and 16 more locations

Time frame: From date of transplant to end of year 3

Number of graft rejections in liver transplant

Cumulative incidence of acute rejection (survival framework) as measured by biopsy using Banff 2016 comprehensive Update for antibody mediated rejection and Banff 1997 criteria for acute cellular rejection, liver.

Time frame: From date of transplant to end of year 3

6-month acute kidney rejection in simultaneous liver/kidney transplant recipients

Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2015 criteria: Borderline changes: 'Suspicious' for acute T-cell mediated rejection.This category is used when no intimal arteritis is present, but there are foci of mild tubulitis (t1, t2, or t3) with minor interstitial infiltration (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1) tubulitis. Acute T-cell mediated rejection:Grade from IA defined as cases with significant interstitial infiltration (\>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2) to III defined as cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3)

Time frame: From date of transplant to 6 months post transplant

1-year acute kidney rejection in simultaneous liver/kidney transplant recipients only

Time frame: From date of transplant to end of year 1

Number of Non-alcoholic fatty liver (NAFL)

Cumulative incidence of NAFL as measured by biopsy and transient elastography with controlled attenuation parameter for steatosis

Time frame: From date of transplant through end of follow-up, up to 3 years

Number of steatohepatitis (NASH)

Cumulative incidence of NASH as measured by biopsy and transient elastography with controlled attenuation parameter for steatosis

Time frame: From date of transplant through end of follow-up, up to 3 years

Trajectory of recipient Cluster of Differentiation (CD4) count over time

Analysis of repeated measures of CD4 (cells/mm3) count (longitudinal model)

Time frame: From date of transplant through end of follow up, up to 4 years

Trajectory of recipient plasma HIV RNA over time

Analysis of repeated measures of plasma HIV RNA (copies/mL) longitudinal model

Time frame: From date of transplant through end of follow-up, up to 4 years

Graft function as assessed by Fibrosis-4 index

Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x √ALT) Fibrosis 4 index estimates the amount of scar or fibrosis in the liver without requiring a biopsy. Using a lower cutoff value of 1.45, a Fibrosis-4 score \<1.45 had a negative predictive value of 90% for advanced fibrosis. In contrast, a Fibrosis-4 \>3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. In the patient cohort in which this formula was first validated, at least 70% patients had values \<1.45 or \>3.25.

Time frame: 1 years post-transplant

Graft function as assessed by Fibrosis-4 index

Time frame: 2 years post-transplant

Graft function as assessed by Fibrosis-4 index

Time frame: 3 years post-transplant

Graft function as assessed by Fibrosis-4 index

Time frame: 4 years post-transplant

Graft function as assessed by incidence of fibrosis

Cumulative incidence of advanced fibrosis (stage F3 or greater as defined by metavir fibrosis score) as measured on biopsy. The fibrosis score is assessed on a five point scale (F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = few septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis).

Time frame: From date of transplant through end of follow-up, up to 3 years

Graft function as assessed by liver stiffness

Mean calculated liver stiffness by transient elastography (kPA)

Time frame: 1 year post-transplant

Graft function as assessed by liver stiffness

Mean calculated liver stiffness by transient elastography (kPA)

Time frame: 2 years post-transplant

Graft function as assessed by liver stiffness

Mean calculated liver stiffness by transient elastography (kPA)

Time frame: 3 years post-transplant

Average graft function as assessed by aspartate aminotransferase (AST)

Mean calculated AST (U/L)

Time frame: 1 year post-transplant

Average graft function as assessed by AST

Mean calculated AST (U/L)

Time frame: 2 years post-transplant

Average graft function as assessed by AST

Mean calculated AST (U/L)

Time frame: 3 years post-transplant

Average graft function as assessed by AST

Mean calculated AST (U/L)

Time frame: 4 years post-transplant

Average graft function as assessed by alanine aminotransferase (ALT)

Mean calculated ALT (U/L)

Time frame: 1 year post-transplant

Average graft function as assessed by ALT

Mean calculated ALT (U/L)

Time frame: 2 years post-transplant

Average Graft function as assessed by ALT

Mean calculated ALT (U/L)

Time frame: 3 years post-transplant

Average graft function as assessed by ALT

Mean calculated ALT (U/L)

Time frame: 4 years post-transplant

Average graft function as assessed by bilirubin

Mean calculated bilirubin (mg/dL)

Time frame: 1 year post-transplant

Average graft function as assessed by bilirubin

Mean calculated bilirubin (mg/dL)

Time frame: 2 years post-transplant

Average graft function as assessed by bilirubin

Mean calculated bilirubin (mg/dL)

Time frame: 3 years post-transplant

Average graft function as assessed by Bilirubin

Mean calculated bilirubin (mg/dL)

Time frame: 4 years post-transplant

Graft function as assessed by Mean calculated Model for End Stage Liver Disease (MELD) score

Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease

Time frame: 1 year post-transplant

Graft function as assessed by Mean calculated MELD score

Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease

Time frame: 2 years post-transplant

Graft function as assessed by Mean calculated MELD score

Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease

Time frame: 3 years post-transplant

Graft function as assessed by Mean calculated MELD score

Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease

Time frame: 4 years post-transplant

Graft function as assessed by AST to Platelet Ratio (APRI) index

Mean calculated APRI index \[( AST / upper limits of normal (ULN) AST ) x 100\] / Platelets (109/L)\] An APRI score greater than 1.0 has a sensitivity of 76% and specificity of 72% for predicting cirrhosis. In addition, APRI score greater than 0.7 has a sensitivity of 77% and specificity of 72% for predicting significant hepatic fibrosis.For detection of cirrhosis, using an APRI cutoff score of 2.0 is more specific (91%) but less sensitive (46%). The lower the APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis); midrange values are less helpful.

Time frame: 1 year post-transplant

Graft function as assessed by AST to Platelet Ratio (APRI) index

Mean calculated APRI index \[( AST / ULN AST ) x 100\] / Platelets (109/L)\] An APRI score greater than 1.0 has a sensitivity of 76% and specificity of 72% for predicting cirrhosis. In addition, APRI score greater than 0.7 has a sensitivity of 77% and specificity of 72% for predicting significant hepatic fibrosis.For detection of cirrhosis, using an APRI cutoff score of 2.0 is more specific (91%) but less sensitive (46%). The lower the APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis); midrange values are less helpful.

Time frame: 2 years post-transplant

Graft function as assessed by AST to Platelet Ratio (APRI) index

Time frame: 3 years post-transplant

Graft function as assessed by AST to Platelet Ratio (APRI) index

Time frame: 4 years post-transplant

Metabolic Outcome as assessed by Body mass index (BMI)

Mean calculated BMI (weight in kilograms/height in meters squared)

Time frame: 1 year post-transplant

Metabolic Outcome as assessed by Body mass index (BMI)

Mean calculated BMI(weight in kilograms/height in meters squared)

Time frame: 2 years post-transplant

Metabolic Outcome as assessed by Body mass index (BMI)

Mean calculated BMI(weight in kilograms/height in meters squared)

Time frame: 3 years post-transplant

Metabolic Outcome as assessed by Body mass index (BMI)

Mean calculated BMI(weight in kilograms/height in meters squared)

Time frame: 4 years post-transplant

Average hemoglobin a1c among participants at 1 year

Mean calculated hemoglobin a1c (mg/dL)

Time frame: 1 years post-transplant

Average hemoglobin a1c among participants at 2 years

Mean calculated hemoglobin a1c (mg/dL)

Time frame: 2 years post-transplant

Average hemoglobin a1c among participants at 3 years

Mean calculated hemoglobin a1c (mg/dL)

Time frame: 3 years post-transplant

Average hemoglobin a1c among participants at 4 years

Mean calculated hemoglobin a1c (mg/dL)

Time frame: 4 years post-transplant

Number of HIV breakthroughs

Measured by local sites' Clinical Laboratory Improvement Amendments (CLIA) certified lab with episode of HIV breakthrough defined as 2 consecutive plasma HIV viral loads \>200 copies/mL or one HIV viral load \>1000 copies/mL after a period of virologic control post-transplant

Time frame: From date of transplant through end of follow-up, up to 4 years

Number of opportunistic infections

Cumulative incidence of opportunistic infections

Time frame: From date of transplant through end of follow-up, up to 4 years

Number of X4 tropic virus breakthroughs

Measured by sending virus at time of breakthrough for HIV co-receptor assay

Time frame: From date of transplant through end of follow-up, up to 4 years

Number of vascular complications

Number of vascular complications within 1 year of transplant, e.g. thrombosis, aneurysm

Time frame: From date of transplant through year 1

Number of surgical complications

Number of surgical complications within 1 year of transplant, e.g. delayed closure, wound dehiscence

Time frame: From date of transplant through year 1

Number of viral-related malignancies

Number of malignancies as determined by local pathology

Time frame: From date of transplant through end of follow-up, up to 4 years

Hepatitis C (HCV) sustained viral response post-transplant

Proportion of HCV RNA positive recipients that achieve a sustained virologic response week 12 post-treatment (\<15 IU/mL) with direct acting antivirals

Time frame: 12 weeks HCV treatment

Number of the formation of de novo donor-specific human leukocyte antigen(HLA) antibodies

Proportion of participants with a de novo donor-specific HLA antibody as measured and reported by local sites' lab

Time frame: From date of transplant through end of year 1

Time to first occurrence of all-cause-mortality or graft failure or renal allograft rejection or HIV breakthrough or HIV virologic failure or AIDS defining illness as a composite measure

Time to first of any of these events: all-cause-mortality or graft failure or renal allograft rejection or HIV breakthrough or HIV virologic failure or AIDS defining illness

Time frame: From date of transplant through end of follow-up, up to 4 years